Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer.

Breast Neoplasms / genetics Case-Control Studies Cell Line, Tumor Cinnamates / pharmacology Collagen / chemistry Drug Combinations Enhancer of Zeste Homolog 2 Protein / genetics Estradiol / pharmacology Estrogen Receptor alpha / genetics Female Fulvestrant / pharmacology Gene Expression Profiling Gene Expression Regulation, Neoplastic Histones / genetics Humans Indazoles / pharmacology Laminin / chemistry Mammary Glands, Human / drug effects Mechanotransduction, Cellular / genetics Phenotype Proteoglycans / chemistry Tamoxifen / pharmacology Tissue Culture Techniques Transcriptome p38 Mitogen-Activated Protein Kinases / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
29 11 2021
Historique:
received: 25 08 2020
accepted: 04 11 2021
entrez: 30 11 2021
pubmed: 1 12 2021
medline: 6 1 2022
Statut: epublish

Résumé

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ERα + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ERα-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ERα + breast cancer models. The ERα + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ERα is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ERα signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ERα phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.

Identifiants

DOI: 10.1038/s41467-021-27220-9 PMID: 34845227 PMC: PMC8630031
pubmed: 34845227
doi: 10.1038/s41467-021-27220-9
pii: 10.1038/s41467-021-27220-9
pmc: PMC8630031
doi:

Substances chimiques

3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0
Cinnamates 0
Drug Combinations 0
ESR1 protein, human 0
Estrogen Receptor alpha 0
Histones 0
Indazoles 0
Laminin 0
Proteoglycans 0
Tamoxifen 094ZI81Y45
matrigel 119978-18-6
Fulvestrant 22X328QOC4
Estradiol 4TI98Z838E
Collagen 9007-34-5
EZH2 protein, human EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43
p38 Mitogen-Activated Protein Kinases EC 2.7.11.24

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

6967

Informations de copyright

© 2021. The Author(s).

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Auteurs

Pauliina M Munne (PM)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-9720-9964

Lahja Martikainen (L)

Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
ORCID: 0000-0002-7092-8467

Iiris Räty (I)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-5241-1368

Kia Bertula (K)

Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
ORCID: 0000-0002-7134-3591
Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
Department of Bioproducts and Biosystems, Aalto University School of Chemical Engineering, Espoo, Finland.
ORCID: 0000-0002-6804-4128

Janika Ruuska (J)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-3978-2033

Hanna Ala-Hongisto (H)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0001-5850-1623

Aino Peura (A)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-8958-940X

Babette Hollmann (B)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.

Lilya Euro (L)

Research Program of Stem Cells and Metabolism, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland.
ORCID: 0000-0001-9705-3886

Kerim Yavuz (K)

Applied Tumor Genomics Research Program, Enhancer Biology Laboratory, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0003-4980-8804

Linda Patrikainen (L)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.

Maria Salmela (M)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.

Juho Pokki (J)

Department of Electrical Engineering and Automation, Aalto University, Espoo, Finland.
ORCID: 0000-0002-3198-7675

Mikko Kivento (M)

Applied Tumor Genomics Research Program, Faculty of Medicine, Oncogenomics Laboratory, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0003-2188-0652

Juho Väänänen (J)

Applied Tumor Genomics Research Program, Faculty of Medicine, Oncogenomics Laboratory, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0001-8857-1411

Tomi Suomi (T)

Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland.
ORCID: 0000-0003-3639-979X

Liina Nevalaita (L)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.
ORCID: 0000-0003-3752-1873

Minna Mutka (M)

Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-8380-7293

Panu Kovanen (P)

Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
ORCID: 0000-0001-8218-2271

Marjut Leidenius (M)

Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.

Tuomo Meretoja (T)

Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.

Katja Hukkinen (K)

Department of Mammography, Helsinki University Central Hospital, Helsinki, Finland.

Outi Monni (O)

Applied Tumor Genomics Research Program, Faculty of Medicine, Oncogenomics Laboratory, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0002-2319-8799

Jeroen Pouwels (J)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland.

Biswajyoti Sahu (B)

Applied Tumor Genomics Research Program, Enhancer Biology Laboratory, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
ORCID: 0000-0001-6576-5440

Johanna Mattson (J)

Department of Oncology, University of Helsinki & Helsinki University Hospital, Helsinki, Finland.
ORCID: 0000-0002-9719-9110

Heikki Joensuu (H)

Department of Oncology, University of Helsinki & Helsinki University Hospital, Helsinki, Finland.
ORCID: 0000-0003-0281-2507

Päivi Heikkilä (P)

Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.

Laura L Elo (LL)

Turku Bioscience Centre, University of Turku and Åbo Akademi University, FI-20520, Turku, Finland.
ORCID: 0000-0001-5648-4532

Ciara Metcalfe (C)

Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.

Melissa R Junttila (MR)

Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.

Olli Ikkala (O)

Department of Applied Physics, Molecular Materials Group, Aalto University School of Science, PO Box, 15100, FI-00076, Espoo, Finland.
Department of Bioproducts and Biosystems, Aalto University School of Chemical Engineering, Espoo, Finland.
ORCID: 0000-0002-0470-1889

Juha Klefström (J)

Finnish Cancer Institute, FICAN South Helsinki University Hospital & Translational Cancer Medicine, Medical Faculty, University of Helsinki. Cancer Cell Circuitry Laboratory, PO Box 63 Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland. Juha.Klefstrom@helsinki.fi.
ORCID: 0000-0001-7124-8431

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Classifications MeSH

questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Compressive stress-mediated p38 activation...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Compressive stress-mediated p38 activation...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Compressive stress-mediated p38 activation...
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